It is important to remember that new drugs are new. In May 2010 Glaxo (GSK) suspended a study with SRT501, Sirtris' formulation of Resveratrol, the minor ingredient in red wine linked to longevity and possible anti-myeloma activity. Now, in December 2010, Fierce Biotech posted that Sirtris (bought by Glaxo for $720 million in 2008) had abandoned SRT501 altogether because of lack of efficacy, and in the case of the myeloma trial, life threatening kidney toxicity. One criticism of the halted myeloma trial was that over ten times the active dose of resveratrol was used and most likely accounted for the kidney toxicity.
Resveratrol is a natural product found in grapes and present in red wine. This natural product is available over the counter, for example, in the Biotivia Transmax product (500mg capsules). The question is whether this natural compound, which extended the life of obese mice in Prof. David Sinclair's original studies, or whether patentable drugs activating just the SIRT I pathway should be the focus for research.1-5 The new synthetic small molecules target the SIRT I pathway whereas the original resveratrol hits many targets which may account for its benefit. And what should the dose be?Assessing anti-aging and possible anti-myeloma effects takes time and patience which is an increasingly rare commodity in the highly charged culture of drug development. The human body is a delicate machine. Giving more of a drug is not necessarily better: maybe there is an ideal lower dose given over time. This was recently illustrated with the impact of a baby aspirin in reducing the occurrence of heart disease and cancer after at least 5 years of use.6-8
Another example is hedgehog inhibitors. 9 Matsui and colleagues10 showed that a critical pathway in the activation of the myeloma stem cell is the Hh (Hedgehog) pathway. Blocking this could prevent myeloma "reseeding" in the bone marrow after successful treatment, and possiblly lead to a cure. A chemical was immediately available capable of blocking the hedgehog gene and called cyclopamine named after the birth defect (of a single eye) in sheep grazing on wild corn lily containing the agent. Again the same story emerged: drug companies tried to replicate the effects of cyclopamine (which has some potentially dangerous side effects) with synthetic compounds. In this case, simply blocking this one pathway turned out to be not that effective in myeloma. But wait, at the recent ASH meeting in Florida another researcher, Dr. Guido Tricot, showed that blocking 2 pathways, Hh plus Wnt, showed remarkable benefit in the laboratory. Tricot tested a combination of cyclopamine plus itraconazole to block Hh and another compound CY10404 (cox-2 inhibitor similar to CelebrexÂ®) to block the additional Wnt pathway. Perhaps persistence and patience can pay off in coming up with an effective strategy.
So new ideas are new. It takes time to figure out the best way forward. This is frustrating, but necessary. The very good news is that these are exciting new ideas and progress is being made. Stay Tuned.
- Wade N. Doubt on Anti-Aging Molecule as Drug Trial Stops, The New York Times; January 11, 2011.
- Saunders LR, Verdin E. Stress response and aging. Science; 323:1021-1022; 2009.
- Brooks CL, Gu W. How does SIRT 1 affect metabolism, senescence and cancer?. Cancer; 9:123-128; 2009.
- Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene; 26:5489-5504; 2007.
- Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature Reviews; 5:493-506; 2006.
- Jacobs EJ. Will an aspirin a day help keep fatal cancer away?. The Lancet; 377:3-4; 2011.
- Rothwell PM, Fowkes FGR, Belch JFF, et al. Effect of daily apsirin on long-term risk of death due to cancer: analysis of individual patient data from randomized trials. The Lancet; 377:31-41; 2011.
- Rothwell PM, Wilson M, Elwin C-E, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomized trials. The Lancet; 376:1741-1750; 2010.
- Low JA, de Sauvage FJ. Clinical experience with hedgehog pathway inhibitors. Journal of Clinical Oncology; 28(36):5321-5326; 2010.
- Matsui, et. al., ASH 2010 "Origin Of The Myeloma Stem Cell", IMF Webcast, http://tinyurl.com/matsuistemcell